The physiological processes of release of lysosomal enzymes from cells, excitation-secretion coupling in adrenal medulla and membrane fusion may include perturbations of participating membranes by activation of phospholipase A. We propose to investigate the contributions of this enzyme and specific structural lipids to these physiological processes that may be modulated by hormonal and pharmacological stimuli. The molecular pathology of ischemic injury to myocardial membranes is poorly understood. We postulate a mechanism of molecular damage to myocardial organelles in ischemia that includes activation of phospholipases A, producing free long-chain fatty acids and lysophospholipids, that may enhance permeability of organelles and perturb the activity of lipid-dependent enzymes. Myocardial ischemia results in losses of lysosomal hydrolases in areas of diminished collateral flow (less than 40%); loss of integrity of the lysosomal membrane probably underlies this process of labilization. Increased sarcolemmal permeability and swelling of the sarcoplasmic reticulum occur early in ischemia. Our preparation of enriched myocardial sarcolemma has phospholipase A activity that may be activated to enhance permeability of this crucial boundary membrane in ischemia. Also, enriched fractions of cardiac sarcoplasmic reticulum have associated phospholipase A activity. Finally, non-myocardial cells (polymorphonuclear leukocytes, platelets and marcophages) contain active phospholipases A that may contribute to ischemic cellular damage. Knowledge of the modulation of activity of phospholipase A and its interaction with structural lipids of membranes may yield information that will be useful in understanding the physiology and pathology of membrane phenomena. In addition, it may permit subsequent infarction.